This invention relates to the treatment of proliferative and pathogenic diseases.
The complement regulatory protein CD59 is expressed on the surface of mammalian cells to protect host cells from the bystander effects of complement activation. CD59 activity inhibits formation of the membrane attack complex of complement (MAC) by binding to complement proteins C8 and C9 and preventing C9 incorporation and polymerization. During maturation by budding, a number of enveloped viruses, such as human cytomegalovirus, HCMV, human T-cell leukemia virus type 1 (HTLV-1), HIV-1, simian immunodeficiency virus, Ebola virus, influenza virus, and vaccinia virus, capture CD59 and use it to evade the complement system (Stoiber et al. Mol. Immunol. 42:153-160 (2005), Bernet et al. J Biosci 28:249-264 (2003), Rautemaa et al. Immunology 106:404-411 (2002), Nguyen et al. J Virol 74:3264-3272 (2000), Saifuddin et al. J. Exp. Med. 182:501-509 (1995), Spiller et al. J Infect Dis 176:339-347 (1997)). Other viruses, (e.g., Herpesvirus saimiri) express a CD59-like molecule that aids the virus in avoiding the complement system. Additionally, microbial parasites have been identified which also express a CD59-like molecule (e.g., Naegleria fowleri and Schistosoma mansoni (Parizade et al. J Exp Med 179:1625-1636 (1994), Fritzinger et al. Infect Immun 74:1189-1195 (2006))). These parasites, many of which are intracellular, are protected from human complement mediated lysis by CD59 and also use CD59 for infectivity (ibid).
Cancer is a disease marked by the uncontrolled growth of abnormal cells. Cancer cells have overcome the barriers imposed in normal cells, which have a finite lifespan, to grow indefinitely. As the growth of cancer cells continues, genetic alterations may persist until the cancerous cell has manifested itself to pursue a more aggressive growth phenotype. If left untreated, metastasis, the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream, may ensue, destroying healthy tissue.
CD59 is over-expressed in many cancer cells. Complement is a main mediator for antibody mediated cancer cytolysis. Up-regulation and high expression of CD59 can drive resistance to any antibody-mediated cancer therapy that activates complement as a component of its mechanism of activity. An example of resistance mediated by CD59 overexpression is resistance to the anti-CD20 chimeric MAb rituximab used for the treatment of B-cell non-Hodgkin lymphoma (B-NHL).
Accordingly, there exists a need for compounds and methods that sensitize pathogens and cancer cells to complement-mediated cell death.